For the next few years, a dramatic increase in oncoses and tumor-related cases of death is expected worldwide. In 2001, worldwide approximately 10 million people were suffering from cancer and over 6 million people died from this disease. The development of tumors is a fundamental disease of higher organisms in flora and fauna. The generally recognized multistep model of carcinogenesis assumes that as a result of accumulation of a number of mutations in an individual cell this is so modified in its proliferation and differentiation behavior that finally, via benign intermediate stages, a malignant, state with metastasis is reached. Behind the term cancer or tumor, a clinical picture with more than 200 various individual diseases hides itself. Oncoses can proceed in a benign or malignant manner. The most important tumors are those of the lung, the breast, the stomach, the neck of the uterus, the prostate, the head and neck, the large and small intestine, the liver and the blood system. There are great differences with respect to course, prognosis and therapy behavior. More than the 90% of the cases recognized relate to solid tumors, which in particular in the advanced stage or on metastasis are treatable with difficulty or untreatable. The three pillars of cancer control are still surgical removal, irradiation and chemotherapy. In spite of great advances it has still not been possible to develop medicaments which bring about a marked prolongation of the survival time or even a complete cure in the widespread solid tumors.
It is therefore meaningful to invent novel medicaments for the control of cancer. In particular, the disadvantageous formation of resistance, as is known of many antitumor agents, should be circumvented.
Indolyl-3-glyoxylamides are frequently used as pharmacologically active compounds and as synthesis components in pharmaceutical chemistry.
In WO03/022280, N-substituted alkyl- and aryl-3-glyoxylamide indoles having antitumoral action are described. Actual exemplary embodiments of this substitution pattern on the glyoxylamide nitrogen atom are, however, not given.
In the documents WO99/51224 A1 and WO01/22954 A1, N-substituted indol-3-yl derivatives having antitumor action are described. Actual exemplary embodiments of this substitution pattern are, however, not given.
In WO99/55696 A1, substituted hydroxyindoles are described as phosphodiesterase 4 inhibitors. An antitumoral activity of the compounds according to the invention is neither described nor suggested.
In WO 02/08225 A1, 2-(1H-indol-3-yl)-2-oxoacetamide derivatives having antitumor action against solid tumors are described. However, the invention does not relate to actual exemplary embodiments with substitution on the glyoxylamide nitrogen atom.
In patent specification WO 00/67802, indole-3-glyoxylamides which are substituted by higher chain fatty acids are described as potential antitumor agents. Actual exemplary embodiments are, however, not given or confirmed by biological data.
In the publication of W.-T. Li et al. (J. Med. Chem. 2003, 46, 1706 ff.), N-heterocyclic indolylglyoxylamides are described as orally active compounds having antitumoral activity.
WO02/10152 A2 of the applicant already describes another class of indole derivatives for the treatment of tumors. Inter alia, the active compound N-(2-methyl-6-quinolyl)-[1-(4-chlorobenzyl)-indol-3-yl]glyoxylamide was tested here on various tumor cell lines for its antiproliferative action.